As a chemotactic substance that induces migration and topical infiltration of leukocytes such as neutrophile, monocyte and the like, there exist classic chemotactic factors such as decomposition products of a complement (e.g., C3a and C5a), metabolites of arachidonic acid (e.g., leukotriene B4 and the like), platelet-activating factors, formylated peptides derived from bacteria, and the like. These are secondary products that mainly accompany tissue injury. In contrast, a series of cytokines produced by a new gene expression, which are responsible for induction and activation of specific leukocytes, i.e., chemokines, were proved to exist by interleukin (IL)-8 (CXCL8) purified and genetically cloned by Matsushima et al. in 1987 (e.g., Proc. Natl. Acad. Sci. USA, vol. 84, pp. 9223–9237 (1987), and J. Exp. Med., vol. 167, pp. 1883–1893 (1988).
To date, 45 kinds of chemokines have been identified and classified into four subgroups based on the characteristics of their amino acid sequences (e.g., immunity, vol. 12, pp. 121–127 (2000)). Namely, C chemokine, CC chemokine, CXC chemokine and CX3C chemokine.
XCL1 belonging to C chemokine has a chemotactic activity for T and NK cells. On the other hand, CC chemokine has a chemotactic activity for monocytes other than neutrophile, lymphocytes, Langerhans cells, dendritic cells, eosinophile, mast cells and basocytes. Furthermore, CXC chemokine mainly acts on neutrophiles, as represented by CXCL8, and CX3C chemokine mainly acts on the migration of NK cells. These chemokines exert their actions when bound with a G protein-coupled receptor (chemokine receptor), and 18 kinds of chemokine receptors have been identified to date (e.g., Cell Technology, vol. 17, pp. 1072–1029, 1998 and Immunity, vol. 12, pp. 121–127, 2000).
Therefore, a substance that prevents binding between chemokine and receptor thereof inhibits selective migration and activation of leukocytes, and is considered to be useful as a pharmaceutical product for the prophylaxis or treatment of acute and chronic inflammatory diseases including allergic diseases, and futher, human immunodeficiency syndrome and the like.
In view of the above, a compound having affinity for a chemokine receptor is expected to be useful as a pharmaceutical product for the prophylaxis or treatment of immune and inflammatory diseases. The present invention aims to provide a pharmaceutical product having affinity for a chemokine receptor and used for treatment or prophylaxis of immune and inflammatory diseases.
With regard to the therapeutic agent of immune and inflammatory diseases, which has affinity for a chemokine receptor, for example, the following patent applications have been published. International publication WO97/24325 discloses diphenylmethane derivatives, WO98/25617 discloses compounds having affinity for a chemokine receptor, such as arylpiperazine derivatives and the like, WO98/02151, WO98/04554 and WO00/34278 disclose tricyclic heteroaromatic derivatives having affinity for a chemokine receptor, and the like, international publications WO99/55324 and WO99/55330 disclose phenylalanine derivatives having affinity for a chemokine receptor, and the like and international publication WO00/58305 discloses piperazine derivatives having affinity for a chemokine receptor, and the like. In addition, international publications WO00/31033, WO00/53600 and WO01/14333 disclose piperidine derivatives and the like, which have affinity for a chemokine receptor.
However, there has been no report to date on a compound having efficacy in a model of allergic disease and the like by oral administration. A compound having efficacy in such disease models and the like is expected to suppresse selective migration and activation of leukocytes and be a pharmaceutical product for the treatment or prophylaxis of acute and chronic inflammatory diseases inclusive of allergic diseases, and further, human immunodeficiency syndrome and the like.